The mouse is the most widely used animal model in studies of cortical development. However, there are very important differences between mouse and human cerebral cortex both in the adult and during development. These important differences undercut the possible relevance of rodent studies for certain aspects of human cortical development, as well as for understanding human neurodevelopmental disorders. Recently, we described new types of neural stem cells found in the developing human brain in a region called the outer subventricular zone. In human brain, this fetal cortical region is very large, and because the cells divide multiple times before giving rise to nerve cells, they greatly increase neuronal output and are chiefly responsible for the huge number of nerve cells in the adult human neocortex. The finding of these novel neural stem and progenitor cells raises important new questions, such as how they contribute to the diversity of cell types found in the adult brain? How cells from this region migrate to reach the cortex? How they contribute to the columns of neurons that are a hallmark of cortical organization? These important questions have the potential to significantly alter our concepts of the development and organization of the human cortex, but they cannot be answered experimentally using human tissue. We propose to address these questions by taking advantage of the ferret, an animal that has a gyrencephalic cortex in the adult and similar neural stem and progenitor cells and similar progenitor zones as humans. We plan to use GFP-tagged retrovirus vectors to infect individual stem and progenitor cells in cortex both in vivo and in vitro. We will then monitor neuronal production and migration by long-term time-lapse imaging, and identify cell types by behavior, morphology, maker expression, and electrophysiological properties. We will determine the pattern of neurogenesis and the lineage of stem and progenitor cells and examine if there is an ontogenetic basis for circuit formation. This information will be necessary if we are to understand a host of developmental disorders of cortical function including autism, schizophrenia, epilepsy, and learning disabilities. PUBLIC HEALTH RELEVANCE: This study investigates the role of outer subventricular zone stem cells (oRGs) and progenitor (IP) cells in the production of cortical neurons in the developing mouse and ferret brain. The subtypes of neural cells produced by traditional radial glia and the newly-described oRG and IP cells are unknown, and neither is the contribution of oRG-derived cells to functional ontogenetic columns in the adult brain. Current models of cortical organization based on discoveries that are decades old do not take oRG cells and their progeny into account. Understanding the developmental organization of the archetypical cortical column in view of the diversity of neural stem and progenitor cells in the developing brain will not only help to explain the functional organization of human neocortex, but will also advance our understanding and potential treatment of a variety of neurodevelopmental disorders including mental retardation, epilepsy, autism, and schizophrenia.